Most cases are X-linked and caused by mutations in a gene on the X chromosome that encodes a protein (CD154, or CD40 ligand) on the surfaces of activated helper T cells. In the presence of cytokines, normal CD40 ligand interacts with B cells and thus signals them to switch from producing IgM to producing IgA, IgG, or IgE. In X-linked hyper-IgM syndrome, T cells lack functional CD40 ligand and cannot signal B cells to switch. Thus, B cells produce only IgM; IgM levels may be normal or elevated.

Patients with this form may have severe neutropenia and often present during infancy with Pneumocystis jirovecii pneumonia. Lymphoid tissue is very small because deficient CD 40 ligand signaling does not activate B cells. Otherwise, clinical presentation is similar to that of X-linked agammaglobulinemia and includes recurrent pyogenic bacterial sinopulmonary infections during the first 2 yr of life. Susceptibility to Cryptosporidium infections may be increased. Many patients die before puberty, and those who live longer often develop cirrhosis or B-cell lymphomas.

In autosomal recessive hyper-IgM syndrome with CD40 mutation, manifestations are similar to those of the X-linked form.

At least 4 autosomal recessive forms involve a B-cell defect. In 2 of these forms (deficiency of activation-induced cytidine deaminase [AID] or uracil DNA glycosylase [UNG]), serum IgM levels are much higher than in the X-linked form; lymphoid hyperplasia (including lymphadenopathy, splenomegaly, and tonsillar hypertrophy) is present, and autoimmune disorders may be present. Leukopenia is absent.